EP2702983A1 - Procédé pour la préparation d'une préparation semi-solide contenant du bispyridiniumalkane - Google Patents

Procédé pour la préparation d'une préparation semi-solide contenant du bispyridiniumalkane Download PDF

Info

Publication number
EP2702983A1
EP2702983A1 EP13179624.5A EP13179624A EP2702983A1 EP 2702983 A1 EP2702983 A1 EP 2702983A1 EP 13179624 A EP13179624 A EP 13179624A EP 2702983 A1 EP2702983 A1 EP 2702983A1
Authority
EP
European Patent Office
Prior art keywords
weight
preparation
bispyridiniumalkane
phase
solution
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP13179624.5A
Other languages
German (de)
English (en)
Other versions
EP2702983B1 (fr
Inventor
Sabine Behrends
Andreas Dettmann
Nadine Radischat
Mona Hahn
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Schuelke and Mayr GmbH
Air Liquide SA
LAir Liquide SA pour lEtude et lExploitation des Procedes Georges Claude
Original Assignee
Schuelke and Mayr GmbH
Air Liquide SA
LAir Liquide SA pour lEtude et lExploitation des Procedes Georges Claude
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schuelke and Mayr GmbH, Air Liquide SA, LAir Liquide SA pour lEtude et lExploitation des Procedes Georges Claude filed Critical Schuelke and Mayr GmbH
Priority to PL13179624T priority Critical patent/PL2702983T3/pl
Publication of EP2702983A1 publication Critical patent/EP2702983A1/fr
Application granted granted Critical
Publication of EP2702983B1 publication Critical patent/EP2702983B1/fr
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4425—Pyridinium derivatives, e.g. pralidoxime, pyridostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to a process for the preparation of a bispyridiniumalkane-containing semisolid preparation.
  • the bispyridiniumalkane is predissolved in a component of the semisolid preparation.
  • the invention relates to the thus prepared semisolid preparation in the form of a concentrate or in the form of a use preparation.
  • the use preparation is applied in particular to the nasal mucous membrane to control multi-resistant pathogens and Gram-negative microorganisms.
  • the invention relates to a kit which comprises the semisolid preparation (in particular the use preparation).
  • Staphylococcus aureus are bacteria which belong to the normal flora of the human skin and mucous membranes. Most frequently, it is the mucous membranes of the pharynx and of the vestibule of the nose which are colonized. Approximately 20% of the population in the Federal Republic of Germany are permanently colonized, and 60% intermittently colonized, with staphylococci. Approximately 0.3 to 5% of the population in Germany are MRSA carriers.
  • the staphylococci are transmitted predominantly via direct contact, in the field of medicine mostly via the hands of patients and staff.
  • the innocuous microbe on the skin may, via injuries, operations, other invasive medical procedures or disturbances of the immune system, penetrate into the human body and cause, inter alia, infections of wounds, soft parts or bones, endocarditis, pneumonia or life-threatening sepsis.
  • Ointments are specific spreadable semisolid preparations which are intended to be employed by application to the skin or rubbing onto the skin. They consist of one or more ointment bases. As a rule, ointments are virtually anhydrous. They have advantages over other pharmaceutical forms in particular when applied to the mucous membrane area, such as, for example, the nose, since they do not dry out the nose, and adhere well to the set application, in particular when the ointment is what is known as an absorption base.
  • An absorption base is a system which is capable of adsorbing water. As a rule, this is achieved by adding specific emulsifiers.
  • Drug substances may be present in the base in dissolved form (solution ointments) or in suspended form (suspension ointments) ( Rudolf Voigt, Pharmazeutician Technologie [Pharmaceutical Technology], 11th edition, page 383 ).
  • solution ointments dissolved form
  • suspension ointments suspended form
  • powders are unsuitable as pharmaceutical forms in the nasal mucosa area because they dry out the nose.
  • Preparations which are used for removing MRSA from the nasopharyngeal zone are those based on mupirocin (pseudomonic acid A).
  • EP 0 231 621 A describes a topical pharmaceutical containing pseudomonic acid and its salts or esters.
  • WO 95/10999 A discloses a composition which comprises a therapeutic agent in a cream base, the cream base comprising 45 to 60% by weight of mineral oil, 5 to 15% by weight of fatty alcohols or fatty esters, 4 to 8% by weight of polyoxyethylene ether or ester surfactant and 20 to 35% by weight of water.
  • WO 98/05313 A relates to a composition which contains mupirocin and chlorhexidin.
  • WO 99/54048 A describes a process and a device for micronizing specially preferred crystalline calcium mupirocin dehydrate.
  • PVP-iodine povidone-iodine
  • the use of PVP-iodine may result in allergies.
  • PVP-iodine may be absorbed. Absorption is a function of the area over which PVP-iodine is used, the amount applied and the use frequency.
  • iodine concentrations which are critical for the hyperthyroid thyroid and, under certain circumstances, even for a euthyroid thyroid can be reached.
  • the contraindications hyperthyroid thyroid diseases and hypersensitivity to iodine must be taken into consideration.
  • WO 2006/029255 A2 describes antimicrobial compositions and processes for their preparation.
  • the compositions may be applied to mucous membranes.
  • the intended cationic antiseptic is, among others, octenidin.
  • a process for the preparation of a formulation containing octenidin is, however, not described in WO 2006/029255 .
  • DE 10 2010 044 785 A1 discloses preparations which are based on a microemulsion with an octenidin content as coemulsifier. The preparations are employed as deodorant formulations, with the octenidin improving the transparency of the microemulsions.
  • DE 10 2010 044 787 A1 maintains that octenidin is not effective in microemulsions with a low active substance content, and that either the active substance content may be increased or that, according to the teaching of DE 10 2010 044 787 A1 , the product should be formulated as a macroemulsion.
  • DE 10 2005 045 145 A1 furthermore discloses semisolid preparations (such as ointments) which contain octenidin dihydrochloride (a bispyridiniumalkane, hereinbelow abbreviated to octenidin), for example in the form of an ointment.
  • octenidin dihydrochloride a bispyridiniumalkane, hereinbelow abbreviated to octenidin
  • bispyridiniumalkanes would be suitable as active substances for controlling MRSA.
  • the ointment base in DE 10 2005 045 145 A1 contains a mixture of wool wax alcohols.
  • Eucerit® (Beiersdorf AG, Hamburg, Federal Republic of Germany) is a mixture of aliphatic alcohols (alkanols with chain lengths of from C 18 to C 20 , diols with chain lengths of from C 16 to C 26 ) and sterols, with a cholesterol content of at least 30%. Wool wax alcohols occasionally contain pesticide residues and may trigger allergies and are therefore undesired.
  • the octenidin nasal ointment concentrate described therein comprises 2.0% by weight of octenidin, 60.0% by weight of wool wax alcohols, 5.0% by weight of cetylstearyl alcohol and 33.0% by weight of soft liquid paraffin.
  • octenidin 60.0% by weight of wool wax alcohols, 5.0% by weight of cetylstearyl alcohol and 33.0% by weight of soft liquid paraffin.
  • one (1) part by weight of the concentrate is formulated together with 9 parts by weight of Vaseline.
  • Octenilin wound gel comprises 0.05% by weight of octenidin, 9.95% by weight of propylene glycol, 2.5% by weight of hydroxyethylcellulose and 87.5% by weight of fully-demineralized water.
  • an antiseptic preparation based on bispyridiniumalkane by means of which MRSA can be controlled effectively, in particular also in the nose. It is intended that the preparation be well tolerated, i.e. no hypersensitivity reactions on the nasal mucosa should occur (in other words, the preparation should not necessarily contain wool wax alcohols). It is intended that the preparation can be formulated as desired, in other words, including as a lipophile preparation, if desired. Furthermore, it should allow control of a wide range of Gram-negative microbes and multi-resistant pathogens (MRPs), in particular MRSA and ESBL producers. Furthermore, it is intended that the preparation be capable of absorbing water from the nasal secretion, which is important for physiological reasons. A particular challenge was furthermore to formulate the system with a low water content. This is important for the system to still be capable of absorbing nasal secretion while still adhering well to the nasal mucosa.
  • MRPs multi-resistant pathogens
  • Another object was therefore also to provide a possibility of incorporating a relatively hydrophilic active substance (bispyridiniumalkane) into an (optionally lipophilic) preparation in such a manner that the preparation has a sufficient antimicrobial activity.
  • a relatively hydrophilic active substance bispyridiniumalkane
  • an ointment base in finely-suspended form.
  • the object was achieved by predissolving the bispyridiniumalkane in a component of the preparation.
  • the invention therefore relates to a process for preparing a semisolid preparation which contains bispyridiniumalkane, in which
  • solution with respect to step a) of the process according to the invention relates to the preparation of a homogeneous liquid mixture, i.e. the bispyridiniumalkane is dissolved completely in the solvent (or solvent mixture).
  • bispyridiniumalkane comprises the bis[4-(substituted-amino)-1-pyridinium]alkanes of the general formulae (I) or (II) disclosed in DE 27 08 331 C2 in which
  • bispyridiniumalkane comprises the various prototropes of the compounds of the formula (I) such as, for example, as disclosed in DE 196 47 692 A1 .
  • Preferred amounts of the bispyridiniumalkane in the semisolid preparation according to the invention are from 0.01 to 1.0% by weight, preferably from 0.02 to 0.5% by weight, more preferably from 0.03 to 0.3% by weight, even more preferably from 0.04 to 0.1% by weight, such as, for example, 0.05% by weight.
  • the temperature in step a) is from 40 to 120°C, more preferably from 50 to 100°C, in particular from 55 to 90°C, for example from 60 to 85°C, such as from 65 to 80°C.
  • the solvent for the bispyridiniumalkane in step a) is preferably selected from among water, polyols and mixtures thereof, with 1,2-propylene glycol, glycerol and mixtures thereof being especially preferred, in particular 1,2-propylene glycol or glycerol. It is clear to a person skilled in the art that the solvent must be compatible with the further formulation components so that the desired semisolid preparation can be formulated.
  • the concentration of the bispyridiniumalkane of the solution prepared in step a) amounts to 0.01 to 5% by weight, preferably 0.02 to 2% by weight, more preferably 0.05 to 1% by weight and in particular 0.1 to 0.5% by weight, based on the weight of the solution.
  • step b) the further usual constituent or the optionally further usual constituents is/are brought to a temperature in the range of from 50 to 100°C (preferably from 60 to 90°C, in particular from 70 to 80°C) and the solution of the bispyridiniumalkane from step a) is then added to the constituent(s), with the solution preferably being added at the same temperature.
  • the solution of step a) is preferably first brought to the temperature of the further constituent(s) and then added at this (same) temperature as the remaining constituent(s).
  • Preferred semisolid preparations according to the invention have good spreadability.
  • the spreadability is determined by the following method:
  • the extent of the oval compressed ointment or emulsion area between the two sheets is determined at two positions (at a 90° angle to each other).
  • the spreadability is then given in mm. The higher this mean, the better the spreadability and therefore the distribution.
  • a semisolid preparation is prepared in the form of a concentrate.
  • the concentrate is characterized in that it can be prepared or is prepared in accordance with the process according to the invention and in that the concentrate contains from 0.1 to 2.0% by weight of bispyridiniumalkane based on the total weight of the concentrate.
  • the semisolid preparation in the form of a use preparation.
  • the use preparation can be prepared or is prepared in accordance with the process according to the invention and it contains from 0.001 to 0.1% by weight of bispyridiniumalkane based on the total weight of the preparation.
  • the invention in further embodiments is a use preparation (in particular in the form of an ointment) which contains from 0.001 to 0.1% by weight of bispyridiniumalkane and whose preparation includes the dissolving of the bispyridiniumalkane in solvent.
  • semisolid preparations according to the invention comprise less than 10% by weight of water, based on their weight.
  • a preferred preparation contains less than 5% by weight of water, more preferably less than 3% by weight of water, such as less than 2% by weight of water.
  • An especially preferred preparation is essentially free from added water, i.e. it contains only the small amount of water which the use of remaining constituents of the semisolid preparation entails.
  • Preferred preparations are free from wool wax alcohols.
  • the preparation according to the invention comprises less than 20% by weight of solvent based on the total weight of the preparation.
  • preferred semisolid preparations are those which contain none of the usual thickeners such as cellulose derivatives, xanthans, pectins, polyacrylates, gelatine or agar.
  • the semisolid preparation (in particular use preparation, such as ointment) can be present as a single-phase or multi-phase embodiment.
  • a multi-phase (preferably two-phase) embodiment it preferably also includes a lipid phase besides the phase in which the bispyridiniumalkane has been predissolved.
  • Constituents of the lipid phase are preferably Vaseline, liquid paraffin, triglycerides and mixtures thereof.
  • Further lipids of the lipid phase may be, for example, beeswax, hard fats, hard waxes, hard paraffin and pig fat.
  • the weight ratio between the solution prepared in step a) and the further constituents added in step b) is, in this context, preferably from 1:99 to 20:80, preferably from 2:98 to 15:85, such as from 5:95 to 10:90.
  • the solvent amounts preferably to from 1 to 15% by weight, but preferably 7 to 12% by weight, especially preferably approximately 10% by weight, based on the weight of the semisolid preparation.
  • HLB hydrophiliclipophilic balance
  • the emulsifier is incorporated either into the phase prepared in step a) or together with the further constituents added in step b).
  • the emulsifier is preferably incorporated together with the constituents added in step b), and no emulsifier is introduced into the phase prepared in step a).
  • emulsifiers are selected from among (partial) esters of (poly)glycerol, for example glycerol (mono,di,tri) [adipate, alkanoate (C 8 , C 10 and C 18 ), isostearate], triglycerol diisostearate, polyglyceryl 2-dipolyhydroxystearate, glyceryl oleate, sorbitan laurate and cetyl stearyl acetate.
  • glycerol mono,di,tri
  • the semisolid preparation in particular use preparation, such as ointment
  • the semisolid preparation according to the invention may additionally comprise antioxidant.
  • antioxidants are disclosed in DE 10 2008 011 691 A1 .
  • Antioxidants which are preferably present and which act in accordance with the invention as stabilizers for bispyridiniumalkanes are acetylcystein, 3-tert-butyl-4-hydroxyanisole, 2,6-di-tert-butyl-p-cresol, tert-butylhydroquinone, caffeic acid, chlorogenic acid, cystein, cystein hydrochloride, decylmercaptomethylimidazole, diamylhydroquinone, di-tert-butylhydroquinone, dicetyl thiodipropionate, digalloyl trioleate, dilauryl thiodipropionate, dimyristyl thiodipropionate, dioleyl tocopheryl methylsilanol, diso
  • the tocopherols are particularly effective antioxidants according to the invention. Furthermore, the tocopherols are particularly desirable antioxidants with regard to the uses of the preparations according to the invention, which are associated with stringent legal provisions and with toxicity tests, in the preparation of cosmetics and pharmaceuticals.
  • Tocopherols are present in vegetable oils. Particularly rich in tocopherols are seed oils from soya, wheat, maize, rice, cotton, lucern and nuts, fruits and vegetables such as raspberries, legumes, fennel, paprika and celery.
  • tocopherols The physiological action of tocopherols is based on their properties as free-radical scavengers.
  • the tocopherols when they are used according to the invention as antioxidants and thus also pass in small amounts into the preparations which contain bispyridiniumalkane, can themselves act as physiologically active antioxidants even in the cell membrane and in lipoproteins.
  • Alpha-tocopherol vitamin E, antisterility factor
  • tocopherols used may be of synthetic origin, tocopherols of natural origin may be used. It is possible to use sterically uniform enantiomers or enantiomer mixtures of tocopherols; accordingly, for the derivatization to acetate, succinate, linoleate or nicotinate, it is possible to use tocopherols of natural and/or synthetic origin and sterically uniform enantiomers or mixtures of tocopherols (in particular alpha-tocopherol).
  • Stabilizers employed in accordance with the invention are preferably selected from among ⁇ -tocopherol, 2,6-di-tert-butyl-4-methylphenol (BHT), tocopherol acetate, 2-tert-butyl-4-hydroxyanisole and/or 3-tert-butyl-4-hydroxyanisole (BHA), dodecyl gallate and ascorbic acid.
  • Preferred stabilizers are vitamin E, vitamin E derivatives, BHA, BHT and alkyl gallate, or combinations of these substances, in particular ⁇ -tocopherol and BHT.
  • the antiseptic preparation according to the invention may, in one embodiment of the invention, be present in the form of a concentrate.
  • the concentrate contains bispyridiniumalkane and solvent, and additionally preferably also at least a part of the remaining constituents of the preparation.
  • the concentrate additionally contains, besides bispyridiniumalkane and solvent, emulsifier and the constituents of a lipid phase.
  • Preferred concentrates contain:
  • Such a concentrate can then (to prepare a use preparation) be mixed with a further lipid phase (for example Vaseline) to obtain the use preparation.
  • a further lipid phase for example Vaseline
  • the preparation according to the invention is prepared in such a way that the bispyridiniumalkane is dissolved in the solvent. Thereafter, the further constituents which may be present are added, for example the constituents of the lipid phase.
  • the constituents of the lipid phase and any emulsifiers may be molten together, and the solution of the bispyridiniumalkane may be added to the melt.
  • An especially preferred use of the preparations according to the invention preparations is the antiseptic treatment of the nose, especially preferably against MRPs (for example MRSA (methicillin-resistant Staphylococcus aureus) and other multi-resistant microbes, such as ESBL).
  • MRPs for example MRSA (methicillin-resistant Staphylococcus aureus) and other multi-resistant microbes, such as ESBL.
  • a further aspect of the invention relates to the preparation for use for controlling Gram-negative microbes and MRPs, specifically MRSA and ESBL, in particular ESBL or MRSA. It is preferred to apply the preparation to the nasal mucosa.
  • kits for controlling Gram-negative microbes and MRPs in particular MRSA and ESBL.
  • a kit according to the invention for the complete semitation of MRP carriers comprises, besides the semisolid preparation according to the invention (in particular use preparation, for example in the form of an ointment) at least one of the following:
  • a preferred rinse for the oropharyngeal cavity (1) is disclosed in DE 10 2006 051 891 A1 and DE 10 2008 011 691 A1 . It is preferred that this rinse comprises the following:
  • Such a rinse (1) is present at a pH of from 5 to 8, such as, preferably, 5.5 to 7.0.
  • the wash lotion (2) contains
  • the constituents (a) to (e) and (h) are combined and dissolved to form a clear solution. Then, the thickener (f) is sprinkled in, and stirring is continued until a clear viscous solution has formed. Then, the organic acid (g) is added and, if appropriate, the pH is adjusted to from 4.8 to 5.0.
  • Softisan 649 partial ester of diglycerol with fatty acids of medium chain length (isostearic acid, stearic acid, 1, 2-hydrostearic acid, adipic acid), (CAS 130 905-60-1), Sasol Germany GmbH, Witten, Federal Republic of Germany.
  • a CSA plate soybean casein digest agar
  • CSA soybean casein digest agar
  • test organism used was an MRSA strain from the DSMZ (Deutsche Sammlung von Mikroorganismen und Zellkulturen [German Collection of Microorganisms and Cell Cultures], Braunschweig, Federal Republic of Germany) (Staphylococcus aureus ATCC 33592).
  • the initial bacterial count of the bacterial suspensions was adjusted as follows: 2 ⁇ 10 5 CFU/ml.
  • the evaluation is carried out via photographic documentation.
  • predissolving the active substance octenidin dihydrochloride improves the activity of the ointment in comparison with the octenidin-containing suspension ointment.
  • the amount applied was in each case 0.10 ml.
  • the evaluation was done via photographic documentation, followed by counting the CFU on each plate and calculating the RF factors based on the blank (plate B13).
  • the Turixin plate shows two microbes, but these are not MRSA, the Turixin plate contains zero (0) microbes. This results in an RF value of 2.83. This RF value is not obtained with the suspension ointments containing octenidin alone (plates B2-B5); the RF values are between 0.38-1.10. The solution ointments generally perform better than the suspension ointments.
  • Formulation B6, which contains 4.95% propylene glycol, has an RF value of 2.53 and therefore approaches the activity of Turixin. Only two microbes grow on the plate. The activity of glycerol-containing formulations (B9 and B11) is good, too; only two and four microbes, respectively, grow. The RF values amount to 2.53 (B9) and 2.23 (B11).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Otolaryngology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP13179624.5A 2012-08-31 2013-08-07 Procédé pour la préparation d'une préparation semi-solide contenant du bispyridiniumalkane Active EP2702983B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PL13179624T PL2702983T3 (pl) 2012-08-31 2013-08-07 Sposób wytwarzania półstałego preparatu zawierającego bispirydynioalkan

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE102012215511.2A DE102012215511A1 (de) 2012-08-31 2012-08-31 Verfahren zur Herstellung einer Bispyridiniumalkan enthaltenden halbfesten Zubereitung

Publications (2)

Publication Number Publication Date
EP2702983A1 true EP2702983A1 (fr) 2014-03-05
EP2702983B1 EP2702983B1 (fr) 2018-10-10

Family

ID=48948295

Family Applications (1)

Application Number Title Priority Date Filing Date
EP13179624.5A Active EP2702983B1 (fr) 2012-08-31 2013-08-07 Procédé pour la préparation d'une préparation semi-solide contenant du bispyridiniumalkane

Country Status (4)

Country Link
EP (1) EP2702983B1 (fr)
DE (1) DE102012215511A1 (fr)
ES (1) ES2702292T3 (fr)
PL (1) PL2702983T3 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019038110A1 (fr) * 2017-08-23 2019-02-28 Schülke & Mayr GmbH Bain de bouche contenant du chlorhydrate d'octénidine
WO2021137102A1 (fr) * 2019-12-31 2021-07-08 3M Innovative Properties Company Articles médicaux antimicrobiens à base de sel d'octénidine

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102014107412A1 (de) 2014-05-26 2015-12-17 Schülke & Mayr GmbH Gefärbte desinfizierende Zubereitung auf Basis von Bispyridiniumalkan
EP3106172B1 (fr) 2015-06-15 2020-08-05 B. Braun Melsungen AG Moyen actif antimicrobien et son utilisation

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0231621A2 (fr) 1985-12-13 1987-08-12 Beecham Group Plc Composition pharmaceutique topique contenant l'acide pseudomonique ou un de ses sels ou esters et un corticostéroide
DE2708331C2 (fr) 1976-02-25 1991-03-21 Sterling Drug Inc., New York, N.Y., Us
WO1995010999A1 (fr) 1993-10-22 1995-04-27 Smithkline Beecham Corporation Nouvelle composition
WO1998005313A1 (fr) 1996-08-01 1998-02-12 Smithkline Beecham Pharmaceuticals (Pty.) Limited Composition contenant de la mupirocine et de la chlorhexidine
DE19647692A1 (de) 1996-11-05 1998-06-04 Schuelke & Mayr Gmbh Waschendes Desinfektionsmittel zur hygienischen und chirurgischen Händedesinfektion
WO1999054048A1 (fr) 1998-04-22 1999-10-28 Smithkline Beecham Plc Procede de micronisation utilisant l'energie d'un fluide, et appareil associe
WO2006029255A2 (fr) 2004-09-07 2006-03-16 3M Innovative Properties Company Compositions antiseptiques cationiques et leurs procedes d'utilisation
DE102005045145A1 (de) 2005-09-15 2007-03-29 Schülke & Mayr GmbH Verwendung von Octenidindihydrochlorid in halbfesten Zubereitungen
DE102006051891A1 (de) 2006-10-31 2008-05-08 Schülke & Mayr GmbH Antimikrobiell wirksame Zusammensetzung mit einem Gehalt an Bispyridiniumalkan
DE102008011691A1 (de) 2008-02-28 2009-09-10 Schülke & Mayr GmbH Stabilisierte, antimikrobiell wirksame Zusammensetzung mit einem Gehalt an Bispyridiniumalkan
US20110091551A1 (en) * 2009-10-15 2011-04-21 Lair Liquide, Societe Anonyme Pour L'etude Et L'exploitation Des Procedes Georges Claude Claude Wound covering comprising octenidine dihydrochloride for use in the antisepsis of catheter insertion points
DE102010044787A1 (de) 2010-09-09 2012-03-15 Beiersdorf Ag Makroemulsionen mit verbesserter Deodorantwirksamkeit
DE102010044785A1 (de) 2010-09-09 2012-03-15 Beiersdorf Ag Octenidindihydrochlorid als Co-Emulgator in Mikroemulsionen

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2708331C2 (fr) 1976-02-25 1991-03-21 Sterling Drug Inc., New York, N.Y., Us
EP0231621A2 (fr) 1985-12-13 1987-08-12 Beecham Group Plc Composition pharmaceutique topique contenant l'acide pseudomonique ou un de ses sels ou esters et un corticostéroide
WO1995010999A1 (fr) 1993-10-22 1995-04-27 Smithkline Beecham Corporation Nouvelle composition
WO1998005313A1 (fr) 1996-08-01 1998-02-12 Smithkline Beecham Pharmaceuticals (Pty.) Limited Composition contenant de la mupirocine et de la chlorhexidine
DE19647692A1 (de) 1996-11-05 1998-06-04 Schuelke & Mayr Gmbh Waschendes Desinfektionsmittel zur hygienischen und chirurgischen Händedesinfektion
WO1999054048A1 (fr) 1998-04-22 1999-10-28 Smithkline Beecham Plc Procede de micronisation utilisant l'energie d'un fluide, et appareil associe
WO2006029255A2 (fr) 2004-09-07 2006-03-16 3M Innovative Properties Company Compositions antiseptiques cationiques et leurs procedes d'utilisation
DE102005045145A1 (de) 2005-09-15 2007-03-29 Schülke & Mayr GmbH Verwendung von Octenidindihydrochlorid in halbfesten Zubereitungen
US20080221165A1 (en) * 2005-09-15 2008-09-11 Air Liquide Sante Use of Octenidine Dihydrochloride in Semisolid Preparations
DE102006051891A1 (de) 2006-10-31 2008-05-08 Schülke & Mayr GmbH Antimikrobiell wirksame Zusammensetzung mit einem Gehalt an Bispyridiniumalkan
DE102008011691A1 (de) 2008-02-28 2009-09-10 Schülke & Mayr GmbH Stabilisierte, antimikrobiell wirksame Zusammensetzung mit einem Gehalt an Bispyridiniumalkan
US20110091551A1 (en) * 2009-10-15 2011-04-21 Lair Liquide, Societe Anonyme Pour L'etude Et L'exploitation Des Procedes Georges Claude Claude Wound covering comprising octenidine dihydrochloride for use in the antisepsis of catheter insertion points
DE102010044787A1 (de) 2010-09-09 2012-03-15 Beiersdorf Ag Makroemulsionen mit verbesserter Deodorantwirksamkeit
DE102010044785A1 (de) 2010-09-09 2012-03-15 Beiersdorf Ag Octenidindihydrochlorid als Co-Emulgator in Mikroemulsionen

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
"RAPA: A novel in vitro method to evaluate antibactericidal skin cleansing products", INTERNATIONAL JOURNAL OF COSMETIC SCIENCE, vol. 32, 2010, pages 107 - 116
N. SLOOT; J. SIEBERT; U. HOFFLER, ZBL. HYG. UMWELTMED., vol. 202, 1999, pages 513 - 523
N.-O. HUBNER ET AL.: "Sanierung von MRSA- positiven Patienten", ARZNEIMITTEL-THERAPIE, vol. 27, 2009, pages 171 - 7
NILS-OLAF HÜBNER ET AL: "Antibiotikafreie Sanierung von MRSA-positivem Personal", GMS KRANKENHAUSHYGIENE INTERDISZIPLINÄR, vol. 4, no. 2, 16 December 2009 (2009-12-16), pages 1/4 - 4/4, XP055089222, DOI: 10.3205/dgkh000129 *
U. ROHR; C. MUELLER; M. WILHELM; G. MUHR; S. GATERMANN, JOURNAL OF HOSPITAL INFECTION, vol. 54, 2003, pages 305 - 309

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019038110A1 (fr) * 2017-08-23 2019-02-28 Schülke & Mayr GmbH Bain de bouche contenant du chlorhydrate d'octénidine
WO2021137102A1 (fr) * 2019-12-31 2021-07-08 3M Innovative Properties Company Articles médicaux antimicrobiens à base de sel d'octénidine
CN114901069A (zh) * 2019-12-31 2022-08-12 3M创新有限公司 奥替尼啶盐抗微生物医疗制品
CN114901069B (zh) * 2019-12-31 2023-10-20 3M创新有限公司 奥替尼啶盐抗微生物医疗制品

Also Published As

Publication number Publication date
EP2702983B1 (fr) 2018-10-10
ES2702292T3 (es) 2019-02-28
DE102012215511A1 (de) 2014-06-12
PL2702983T3 (pl) 2019-05-31

Similar Documents

Publication Publication Date Title
EP2702983B1 (fr) Procédé pour la préparation d'une préparation semi-solide contenant du bispyridiniumalkane
AU2017200040B2 (en) Semisolid aqueous pharmaceutical composition containing tapentadol
KR101658116B1 (ko) 에멀젼계 치료학적 국소 제형용 보존 시스템
WO2012011566A1 (fr) Composition crémeuse de type huile dans eau contenant du tacrolimus
JP2017226664A (ja) Ｄｇｌａ、１５−ｏｈｅｐａおよび／または１５−ｈｅｔｒｅを含む医薬組成物、ならびにその使用方法
EP3205211B1 (fr) Composition antivirale à base d'alcool
JP7148994B2 (ja) ビスホスホシンゲル製剤及びその使用
AU2014257984B2 (en) Composition for use in reducing scab formation and promoting healing
JP6987039B2 (ja) 抗菌剤と組み合わせた中極性油の細菌性バイオフィルムに対する相乗的抗菌活性
WO2011055139A2 (fr) Préparations
WO2009106467A2 (fr) Composition stabilisée à efficacité antimicrobienne présentant une teneur en bispyridinium-alcane
US20190336517A1 (en) Compositions for the treatment of dermatological diseases and disorders
WO2004105492A1 (fr) Compositions aqueuses destinees a la desinfection et/ou sterilisation
CA2711114A1 (fr) Compositions topiques pour l'administration controlee de proteines et de peptides
JPH11199476A (ja) 消毒及び／又は殺菌用組成物
JP5674786B2 (ja) タクロリムスを含有する水中油型クリーム状組成物
CN105395473B (zh) 盐酸克林霉素乳膏及其制备方法
TW202228661A (zh) 外用組成物
TWI474841B (zh) 乳劑基治療局部製劑的保存系統
WO2010003431A1 (fr) Composition de désinfection

Legal Events

Date Code Title Description
AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20140905

RBV Designated contracting states (corrected)

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

17Q First examination report despatched

Effective date: 20151218

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

INTG Intention to grant announced

Effective date: 20180319

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE PATENT HAS BEEN GRANTED

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

Ref country code: AT

Ref legal event code: REF

Ref document number: 1050413

Country of ref document: AT

Kind code of ref document: T

Effective date: 20181015

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602013044762

Country of ref document: DE

REG Reference to a national code

Ref country code: NL

Ref legal event code: MP

Effective date: 20181010

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG4D

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2702292

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20190228

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 1050413

Country of ref document: AT

Kind code of ref document: T

Effective date: 20181010

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20181010

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20181010

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190210

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190110

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20181010

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20181010

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190110

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20181010

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20181010

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: RS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20181010

Ref country code: AL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20181010

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20181010

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190210

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190111

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602013044762

Country of ref document: DE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20181010

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20181010

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20181010

Ref country code: SM

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20181010

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20181010

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20181010

REG Reference to a national code

Ref country code: ES

Ref legal event code: PC2A

Owner name: SCHUELKE & MAYR GMBH

Effective date: 20190827

26N No opposition filed

Effective date: 20190711

REG Reference to a national code

Ref country code: GB

Ref legal event code: 732E

Free format text: REGISTERED BETWEEN 20190919 AND 20190925

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20181010

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20181010

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190807

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190831

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190831

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20181010

REG Reference to a national code

Ref country code: BE

Ref legal event code: MM

Effective date: 20190831

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190807

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190831

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20181010

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20181010

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO

Effective date: 20130807

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20181010

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20220819

Year of fee payment: 10

Ref country code: GB

Payment date: 20220822

Year of fee payment: 10

Ref country code: DE

Payment date: 20220819

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: PL

Payment date: 20220801

Year of fee payment: 10

Ref country code: FR

Payment date: 20220823

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20221024

Year of fee payment: 10

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 602013044762

Country of ref document: DE

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20230807

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230807

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230807

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230807

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230831

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20240301

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20240927